Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients

doi:10.1007/s11684-023-0997-7

Front. Med.

2023, Vol. 17

Issue (6) : 1236-1249 https://doi.org/10.1007/s11684-023-0997-7

Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients

Xinyue Zhao¹, Haijun Ge¹, Wenshuai Xu¹, Chongsheng Cheng², Wangji Zhou², Yan Xu², Junping Fan², Yaping Liu¹(

), Xinlun Tian²(

), Kai-Feng Xu², Xue Zhang¹

¹. McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China
². Department of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China

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Abstract

Primary ciliary dyskinesia (PCD) is a highly heterogeneous recessive inherited disorder. FAP54, the homolog of CFAP54 in Chlamydomonas reinhardtii, was previously demonstrated as the C1d projection of the central microtubule apparatus of flagella. A Cfap54 knockout mouse model was then reported to have PCD-relevant phenotypes. Through whole-exome sequencing, compound heterozygous variants c.2649_2657delinC (p. E883Dfs*47) and c.7312_7313insCGCAGGCTGAATTCTTGG (p. T2438delinsTQAEFLA) in a new suspected PCD-relevant gene, CFAP54, were identified in an individual with PCD. Two missense variants, c.4112A>C (p. E1371A) and c.6559C>T (p. P2187S), in CFAP54 were detected in another unrelated patient. In this study, a minigene assay was conducted on the frameshift mutation showing a reduction in mRNA expression. In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses. Correspondingly, two missense variants were deleterious, with a dramatic reduction in mRNA abundance from bronchial tissue and sperm. The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene. This study further helps expand the disease-associated gene spectrum and improve genetic testing for PCD diagnosis in the future.

Keywords primary ciliary dyskinesia CFAP54 cilia

Corresponding Author(s): Yaping Liu,Xinlun Tian

Just Accepted Date: 30 August 2023 Online First Date: 19 September 2023 Issue Date: 06 February 2024

Cite this article:

Xinyue Zhao,Haijun Ge,Wenshuai Xu, et al. Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients[J]. Front. Med., 2023, 17(6): 1236-1249.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-0997-7
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I6/1236

Fig.1 Mutations of CFAP54 in patient with primary ciliary dyskinesia (PCD) with abnormal sperm. (A) Family pedigree chart for patients from F1. The male proband has a sister who also had bronchiectasis and chronic sinusitis and was suspected to have PCD. (B) Thoracic computed tomography of the proband of F1 showing slight bronchiectasis in both lower lobes (marked as red arrow) and atelectasis in the right middle lobe (marked as yellow arrowhead). (C) Sanger sequencing revealing a frameshift deletion, c.2649_2657delinC (p. E883Dfs*47), and a non-frameshift insertion, c.7312_7313insCGCAGGCTGAATTCTTGG (p. T2438delinsTQAEFLA), in CFAP54 and two variants’ parental origins. (D) Morphology of sperm from a healthy individual and a patient with PCD, as observed by H&E staining under microscopy. Compared with the normal sperm, the flagella of patient’s sperm were either short or absent, and the sperm head was congregated. (E) TEM results of the ultrastructure of patient’s sperm flagella. Incomplete “9+2” structure was observed. (F) qPCR analysis showing statistically significant reduction in CFAP54 mRNA expression of patient’s sperm.

Fig.2 Minigene assay and qPCR for frameshift deletion. (A) Diagram of the minigene assay by In-Fusion cloning method. Exon 20 and the flanking intronic region of CFAP54 with or without the frameshift mutation were cloned into the pCAS2 plasmid. The constant sequence of exon A and exon B can be transcribed into cDNA. The transcription of exon A + exon 20 + exon B was regulated by the T7 promotor (symbolized by arrowhead). The transcription of neomycin ORF was regulated by the SV40 promotor separately. The black arrow pairs show the primer pairs of the internal control and target sequence. (B) qPCR results of wild-type and mutant plasmids. Compared with the wild type, the mutant plasmid showed a dramatic decrease in the expression of exon A + exon 20 + exon B transcription. (C) Transcription product verified by Sanger sequencing.

Fig.3 Hydrocephalus in Cfap54^ki/ki mouse model. (A) Diagram of Cfap54 non-frameshift mutation c.7535_7536delinCGCAGGCTGAATTCTTGGCA knock-in by the CRISPR/Cas9 method. The genotype of the Cfap54^ki/ki (HO) mouse model was verified by Sanger sequencing. (B) Survival rates of Cfap54^ki/ki, Cfap54^ki/wt (HE), and Cfap54^wt/wt mice (WT). The birth rate of the offspring produced by mating between HE mice was consistent with the Mendelian ratio of 1:2:1 (nWT:nHE:nHO = 24:54:23, number of mice remaining shown in the first column at day 0). HO mice showed signs of early mortality, and more than half of them died naturally before 60 days of age (number of mice remaining shown in the third column (day 60) and the second line (HO mice)), potentially due to severe hydrocephalus. Log-rank test was used to analyze the differences between survival rates. (C) Body observation of WT and HO mice, which showed HO mice to have an enlarged cranial vault, highlighted by orange arrowheads. (D–G) Hydrocephalus in the lateral ventricles of HO mice compared with WT mice (n = 3 WT, n = 3 HO). The severity of hydrocephalus varied between the two mutant mice (E) and (G), implicating individual differences in phenotypes.

Fig.4 Sinusitis in Cfap54^ki/ki mouse model. (A) H&E staining results of nasal sinuses from one wild-type (WT) and two mutant (HO) mice. NS, ES, and MS indicate the nasal septum, ethmoidal sinuses, and maxillary sinuses, respectively. The red asterisks highlight the accumulation of red-stained mucus. Compared with the WT mice, in which the nasal passage and sinuses were clean, the HO mice showed mucus accumulation in the nasal passage, maxillary sinuses, and ethmoidal sinuses. (B–E) Mucus accumulation revealed by MRI (n = 3 WT, n = 3 HO), as indicated by red asterisks. The HO mice (C) and (E) showed individual differences in sinusitis. (F) H&E staining results from five WT, four HE, and seven HO mice. Mice with mucus accumulation in the nasal sinuses and/or a dramatically distorted nasal septum were assessed as having sinus abnormalities. (G) Box plot of CBF from WT and HO respiratory cilia (n = 6 WT, n = 6 HO). The HO cilia shows a decreased median value of CBF from 8.2 Hz (mean value of 8.2 Hz with a sample standard deviation of 3.5 Hz) to 6.2 Hz (mean value of 7.0 Hz with a sample standard deviation of 3.1 Hz) compared with the WT cilia, and the difference is statistically significant, with P value less than 1.00e–04 according to Mann–Whitney U test.

Fig.5 Infertility in Cfap54^ki/ki mouse model. (A–D) H&E staining results of testes from wild-type (WT) and mutant (HO) mice (n = 3 WT, n = 3 HO). The spermatids of WT mice elongated during spermiogenesis, and sperm flagella extended into the lumen of seminiferous tubules. By contrast, the HO mice exhibited a reduction in the number of flagella in the lumen. Orange arrows point to the hooked sperm heads, and red asterisks indicate empty seminiferous tubule lumens. (E) The morphology of sperm from the epididymis was observed by H&E staining under microscopy (n = 3 WT, n = 3 HO). Compared with WT sperm, which had a hooked head linked by smooth and elongated flagella with normal length, the HO sperm had either short or absent flagella. (F) TEM results of the ultrastructure of sperm flagella (n = 2 WT, n = 2 HO). In WT mice, the normal cross-sections of flagella were recognized as a “9+2” structure surrounded by outer dense fibers of sperm. By contrast, the sperm flagella from the testes of Cfap54^ki/ki mice were abnormally assembled and completely disorganized. (G) qPCR analysis showing a statistically significant reduction in mRNA expression of Cfap54 in the testes and brain of WT and HO mice (n = 3 WT, n = 3 HO).

Tab.1 Missense mutations in CFAP54 in patients with PCD

Fig.6 Pedigree of the family and mutations identified in F2 individual with PCD. (A) Pedigree of PCD F2 with inherited CFAP54 pathogenic variants. Black arrow, proband. (B) Thoracic computed tomography showing slight bilateral lower lung-predominant bronchiectasis and typical imaging manifestations, such as the signet ring sign (red arrows). (C) Protein interaction network predicted to reveal functional partners by STRING for human CFAP54 (also known as C12orf55 in the center) protein. A potential functional partner was predicted between human CFAP54 and CCDC39. Yellow and black lines suggest the predictions from text mining and co-expression, respectively. (D) Sanger-sequencing chromatograms of PCD-affected individual who carries compound heterozygous missense mutations c.4112A>C (p. E1371A) and c.6559C>T (p. P2187S). (E) Evolutionary conservation analysis conducted in eight mammals via Multalin tool. Mutated residues 1371E and 2187P are indicated by black boxes, high-consensus residues are shown in red, low-consensus residues are shown in blue, and neutral residues are shown in black.

Fig.7 Expression analysis of CFAP54 mRNA in bronchial tissue and sperm from PCD individuals and controls. (A) qPCR analysis revealing that the abundance of CFAP54 mRNA extracted from bronchial tissues was significantly reduced in PCD individuals harboring CFAP54 compound heterozygous mutations compared with three unrelated normal controls (N1, N2, and N3). (B) Decreased abundance of CFAP54 mRNA extracted from sperm based on qPCR analysis from PCD individuals compared with a control male. The means ± standard error of measurement of three independent technical replicates are presented, and t tests were performed as appropriate.

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